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Andrew J. White, Elizabeth Kelly, Paul R. Healey, Hans Zoellner; P-Glycoprotein Blockers Potentiate the Effect of Mitomycin C on Human Tenon Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3113.
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Mitomycin C is frequently used to retard wound healing after glaucoma surgery. High dose Mitomycin C substantially increases toxicity-related complications. There is potential benefit from either replacement of Mitomycin C or adjunctive use of agents that increase its therapeutic activity when used at a low dose. We investigated the effect upon Mitomycin C induced apoptosis of agents inhibiting channel p-glycoprotein activity in primary human tenon fibroblast cell culture.
Fibroblast cell lines were established by explant culture from human tissue biopsy samples obtained during trabeculectomy procedures. Cells were exposed to mitomycin C at varying concentrations (0.01 - 0.4 mg/ml) for 3 minutes, prior to washing in the presence or absence of the following drugs: Staurosporine (0.003mg/ml); Verapamil (2.5 - 0.25mg/ml); or cyclosporine (50 - 0.5mg/ml). All are thought to bind and inhibit activity of P-gp for separate P-gp substrates. Following exposure, cells were cultured for 6 Hrs and surviving cells counted using a haemocytometer.
Both verapamil and staurosporine exhibited mild toxic effects on their own but greatly enhanced the apoptotic effect of Mitomycin C. Low doses of verapamil were used to mimic a clinically acceptable dose administered topically. Doses as low as 0.25mg/ml verapamil continued to show significant augmentation of the apoptotic effect of mitomycin C. Cyclosporine 0.5mg/ml (the concentration commercially available in dry eye medication) modestly augmented of the effect of mitomycin C.
Verapamil and Cyclosporine in clinically acceptable concentrations potentiate the effect of Mitomycin C and may obviate the need for high dose anti-metabolites in trabeculectomy.
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